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Front Immunol ; 10: 2449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824476


Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by mucosa damage associated with an uncontrolled inflammatory response. This immunological impairment leads to altered inflammatory mediators such as IL-33, which is shown to increase in the mucosa of active UC (aUC) patients. MicroRNAs present a distorted feature in inflamed colonic mucosa and are potential IL-33 regulating candidates in UC. Therefore, we studied the microRNA and mRNA profiles in inflamed colonic samples of UC patients, evaluating the effect of a microRNA (selected by in silico analysis and its expression in UC patients), on IL-33 under inflammatory conditions. We found that inflamed mucosa (n = 8) showed increased expression of 40 microRNAs and 2,120 mRNAs, while 49 microRNAs and 1,734 mRNAs were decreased, as determined by microarrays. In particular, IL-33 mRNA showed a 3.8-fold increase and eight members of a microRNA family (miR-378), which targets IL-33 mRNA in the 3'UTR, were decreased (-3.9 to -3.0 times). We selected three members of the miR-378 family (miR-378a-3p, miR-422a, and miR-378c) according to background information and interaction energy analysis, for further correlation analyses with IL-33 expression through qPCR and ELISA, respectively. We determined that aUC (n = 24) showed high IL-33 levels, and decreased expression of miR-378a-3p and miR-422a compared to inactive UC (n = 10) and controls (n = 6). Moreover, both microRNAs were inversely correlated with IL-33 expression, while miR-378c does not show a significant difference. To evaluate the effect of TNFα on the studied microRNAs, aUC patients with anti-TNF therapy were compared to aUC receiving other treatments. The levels of miR-378a-3p and miR-378c were higher in aUC patients with anti-TNF. Based on these findings, we selected miR-378a-3p to exploring the molecular mechanism involved by in vitro assays, showing that over-expression of miR-378a-3p decreased the levels of an IL-33 target sequence ß-gal-reporter gene in HEK293 cells. Stable miR-378a-3p over-expression/inhibition inversely modulated IL-33 content and altered viability of HT-29 cells. Additionally, in an inflammatory context, TNFα decreased miR-378a-3p levels in HT-29 cells enhancing IL-33 expression. Together, our results propose a regulatory mechanism of IL-33 expression exerted by miR-378a-3p in an inflammatory environment, contributing to the understanding of UC pathogenesis.

Front Immunol ; 10: 1394, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281317


In colorectal cancer (CRC), cancer-associated fibroblasts (CAFs) are the most abundant component from the tumor microenvironment (TM). CAFs facilitate tumor progression by inducing angiogenesis, immune suppression and invasion, thus altering the organization/composition of the extracellular matrix (i.e., desmoplasia) and/or activating epithelial-mesenchymal transition (EMT). Soluble factors from the TM can also contribute to cell invasion through secretion of cytokines and recently, IL-33/ST2 pathway has gained huge interest as a protumor alarmin, promoting progression to metastasis by inducing changes in TM. Hence, we analyzed IL-33 and ST2 content in tumor and healthy tissue lysates and plasma from CRC patients. Tissue localization and distribution of these molecules was evaluated by immunohistochemistry (using localization reference markers α-smooth muscle actin or α-SMA and E-cadherin), and clinical/histopathological information was obtained from CRC patients. In vitro experiments were conducted in primary cultures of CAFs and normal fibroblasts (NFs) isolated from tumor and healthy tissue taken from CRC patients. Additionally, migration and proliferation analysis were performed in HT29 and HCT116 cell lines. It was found that IL-33 content increases in left-sided CRC patients with lymphatic metastasis, with localization in tumor epithelia associated with abundant desmoplasia. Although ST2 content showed similarities between tumor and healthy tissue, a decreased immunoreactivity was observed in left-sided tumor stroma, associated to metastasis related factors (advanced stages, abundant desmoplasia, and presence of tumor budding). A principal component analysis (including stromal and epithelial IL-33/ST2 and α-SMA immunoreactivity with extent of desmoplasia) allowed us to distinguish clusters of low, intermediate and abundant desmoplasia, with potential to develop a diagnostic signature with benefits for further therapeutic targets. IL-33 transcript levels from CAFs directly correlated with CRC cell line migration induced by CAFs conditioned media, with rhIL-33 inducing a mesenchymal phenotype in HT29 cells. These results indicate a role of IL-33/ST2 in tumor microenvironment, specifically in the interaction between CAFs and epithelial tumor cells, thus contributing to invasion and metastasis in left-sided CRC, most likely by activating desmoplasia.

Front Immunol ; 10: 277, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30915065


Ulcerative colitis (UC) and Crohn's disease (CD), collectively known as Inflammatory Bowel Diseases (IBD), are caused by a complex interplay between genetic, immunologic, microbial and environmental factors. Dysbiosis of the gut microbiome is increasingly considered to be causatively related to IBD and is strongly affected by components of a Western life style. Bacteria that ferment fibers and produce short chain fatty acids (SCFAs) are typically reduced in mucosa and feces of patients with IBD, as compared to healthy individuals. SCFAs, such as acetate, propionate and butyrate, are important metabolites in maintaining intestinal homeostasis. Several studies have indeed shown that fecal SCFAs levels are reduced in active IBD. SCFAs are an important fuel for intestinal epithelial cells and are known to strengthen the gut barrier function. Recent findings, however, show that SCFAs, and in particular butyrate, also have important immunomodulatory functions. Absorption of SCFAs is facilitated by substrate transporters like MCT1 and SMCT1 to promote cellular metabolism. Moreover, SCFAs may signal through cell surface G-protein coupled receptors (GPCRs), like GPR41, GPR43, and GPR109A, to activate signaling cascades that control immune functions. Transgenic mouse models support the key role of these GPCRs in controlling intestinal inflammation. Here, we present an overview of microbial SCFAs production and their effects on the intestinal mucosa with specific emphasis on their relevance for IBD. Moreover, we discuss the therapeutic potential of SCFAs for IBD, either applied directly or by stimulating SCFAs-producing bacteria through pre- or probiotic approaches.

Tumour Biol ; 40(11): 1010428318810059, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30419802


A complex network of chemokines can influence cancer progression with the recruitment and activation of hematopoietic cells, including macrophages to the supporting tumor stroma promoting carcinogenesis and metastasis. The aim of this study was to investigate the relation between tissue and plasma chemokine levels involved in macrophage recruitment with tumor-associated macrophage profile markers and clinicopathological features such as tumor-node-metastases stage, desmoplasia, tumor necrosis factor-α, and vascular endothelial growth factor plasma content. Plasma and tumor/healthy mucosa were obtained from Chilean patients undergoing colon cancer surgery. Chemokines were evaluated from tissue lysates (CCL2, CCL3, CCL4, CCL5, and CX3CL1) by Luminex. Statistical analysis was performed using Wilcoxon match-paired test ( p < 0.05). Macrophage markers (CD68, CD163, and iNOS) were evaluated by immunohistochemistry samples derived from colorectal cancer patients. Correlation analysis between chemokines and macrophage markers and clinicopathological features were performed using Spearman's test. Plasmatic levels of chemokines and inflammatory mediators' vascular endothelial growth factor and tumor necrosis factor-α were evaluated by Luminex. Tumor levels of CCL2 (mean ± standard deviation = 530.1 ± 613.9 pg/mg), CCL3 (102.7 ± 106.0 pg/mg), and CCL4 (64.98 ± 48.09 pg/mg) were higher than those found in healthy tissue (182.1 ± 116.5, 26.79 ± 22.40, and 27.06 ± 23.69 pg/mg, respectively p < 0.05). The tumor characterization allowed us to identify a positive correlation between CCL4 and the pro-tumor macrophages marker CD163 ( p = 0.0443), and a negative correlation of iNOS with desmoplastic reaction ( p = 0.0467). Moreover, we identified that tumors with immature desmoplasia have a higher CD163 density compared to those with a mature/intermediated stromal tissue ( p = 0.0288). Plasmatic CCL4 has shown a positive correlation with inflammatory mediators (tumor necrosis factor-α and vascular endothelial growth factor) that have previously been associated with poor prognosis in patients. In conclusion High expression of CCL4 in colon cancer could induce the infiltration of tumor-associated macrophages and specifically a pro-tumor macrophage profile (CD163+ cells). Moreover, plasmatic chemokines could be considered inflammatory mediators associated to CRC progression as well as tumor necrosis factor-α and vascular endothelial growth factor. These data reinforce the idea of chemokines as potential therapeutic targets or biomarker in CRC.

Biomarcadores Tumorais/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CCL3/metabolismo , Quimiocina CCL4/metabolismo , Neoplasias Colorretais/patologia , Macrófagos/patologia , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Neoplasias Colorretais/metabolismo , Feminino , Seguimentos , Humanos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico
J Neurogastroenterol Motil ; 23(2): 273-280, 2017 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-27669829


Background/Aims: Chronic intestinal pseudo-obstruction (CIPO) is a rare syndrome characterized by a failure of the propulsion of intraluminal contents and recurrent symptoms of partial bowel obstruction in the absence of mechanical obstruction. Regional variations of the intestinal compromise have been described. Intestinal manometry can indicate the pathophysiology and prognosis. Our objective is to establish the demographic and clinical characteristics of group Chilean patients and analyze the motility of the small intestine and its prognostic value. Methods: Patients with symptoms of intestinal pseudo-obstruction with dilated bowel loops were included, in all of whom a manometry of the small intestine was performed using perfused catheters. Results: Of the 64 patients included, 51 women (average age 41.5 ± 17.6 years), 54 primary and 10 secondary CIPO were included. Dilatation of the small intestine was the only finding in 38 patients; in the remaining, the compromise was associated with other segments, primarily the colon. Forty-nine patients underwent 65 surgeries, mainly exploratory laparotomies and colectomies. Intestinal manometry was performed on all patients; 4 "patterns" were observed: neuropathic (n = 26), myopathic (n = 3), mixed (n = 24), and a group without motor activity (n = 11). The most relevant findings were the complex migrating motor disorders and decreased frequency and propagation of contractions. The 9 patients who died had a severe myopathic compromise. Conclusions: In our series, isolated small bowel compromise was the most common disorder. Neuropathic motor compromise was observed in most of the patients. Mortality was associated with severe myopathic compromise.

BMC Gastroenterol ; 16: 103, 2016 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-27565556


BACKGROUND: The ST2/IL-33 pathway has been related to ulcerative colitis (UC), and soluble ST2 (sST2), to disease severity. We tested the potential usefulness of sST2 as a predictive marker of treatment response and patients' outcome. METHODS: Twenty-six patients with active UC were prospectively recruited and grouped according to an endoscopic score and therapy response. Colonoscopic biopsies were collected at baseline and 6 months or when patients showed clinical activity. The protocol was reinitiated in patients requiring rescue therapy. Blood and stool were collected at baseline, 1, 3, 6 and 12 months. Serum and mucosal ST2, and fecal calprotectin (FC) content were determined by ELISA and correlated to Mayo clinical and endoscopic subscore. Intestinal ST2 was evaluated by immunofluorescence. Wilcoxon signed rank test and Spearman correlations (Rs) were applied (p <0.05). RESULTS: Follow-up was completed in 24 patients. sST2 levels (median and range) varied from 173.5 [136.6-274.0] to 86.5 [54.6-133.2] in responders (p < 0.05), and 336.3 [211.0-403.2] to 385.3 pg/mL [283.4-517.3] in non-responders at baseline and 6 months, respectively. sST2 levels correlated with Mayo clinical and endoscopic subscore, mucosal ST2 and FC (Rs = 0.57, 0.66, 0.74 and 0.42, respectively; p < 0.0001) and showed a trend similar to that of FC in responders. Non-responders revealed an increased ST2 content, restricted to the lamina propria's cellular infiltrate. CONCLUSIONS: Consecutive sST2 measurement to follow changes in inflammatory activity of UC patients who respond or not to treatment identifies sST2, like FC, as a useful biomarker in predicting clinical outcome of UC patients.

Colite Ulcerativa/sangue , Colite Ulcerativa/patologia , Proteína 1 Semelhante a Receptor de Interleucina-1/análise , Adulto , Biomarcadores/análise , Biópsia/métodos , Colite Ulcerativa/terapia , Colonoscopia , Ensaio de Imunoadsorção Enzimática , Fezes/química , Feminino , Imunofluorescência , Humanos , Mucosa Intestinal/patologia , Complexo Antígeno L1 Leucocitário/análise , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Estatísticas não Paramétricas
J Immunol Res ; 2014: 149185, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24901008


Acute inflammation is a response to an alteration induced by a pathogen or a physical or chemical insult, which functions to eliminate the source of the damage and restore homeostasis to the affected tissue. However, chronic inflammation triggers cellular events that can promote malignant transformation of cells and carcinogenesis. Several inflammatory mediators, such as TNF-α, IL-6, TGF-ß, and IL-10, have been shown to participate in both the initiation and progression of cancer. In this review, we explore the role of these cytokines in important events of carcinogenesis, such as their capacity to generate reactive oxygen and nitrogen species, their potential mutagenic effect, and their involvement in mechanisms for epithelial mesenchymal transition, angiogenesis, and metastasis. Finally, we will provide an in-depth analysis of the participation of these cytokines in two types of cancer attributable to chronic inflammatory disease: colitis-associated colorectal cancer and cholangiocarcinoma.

Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Colite/metabolismo , Neoplasias Colorretais/metabolismo , Microambiente Tumoral/genética , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Carcinogênese/genética , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Doença Crônica , Colite/complicações , Colite/genética , Colite/patologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Expressão Gênica , Humanos , Inflamação/complicações , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Estresse Oxidativo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
Dig Dis Sci ; 57(5): 1330-5, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22297652


BACKGROUND: The role of small intestinal bacterial overgrowth (SIBO) in functional digestive disorders in the pediatric population is a matter of controversy, since methods currently used to establish this diagnosis are difficult to interpret. The aim of this work was to analyze the characteristics of the lactulose H(2) breath test (LHBT) in children with functional gastrointestinal symptoms according to more recent criteria. METHODS: Seventy-two patients and 17 controls were enrolled. A questionnaire was administered regarding digestive symptoms (abdominal pain, bloating, vomiting, and bowel-movement disorders). A lactose hydrogen breath test was performed to rule out lactose malabsorption and a LHBT was used to measure the time elapsed between lactulose oral ingestion and an increment of H(2) concentration of 20 ppm over basal. RESULTS: There were no differences of age and gender between patients and controls. Mean time to 20-ppm change was shorter in patients (56.3 ± 3 min) compared to healthy children (74.7 ± 5 min), p\0.05. In 39% of patients, rise of H(2) occurred during the first 40 min after lactulose ingestion, and in almost all controls, an increment was observed between 50 and 90 min (p\0.05). Symptoms were unrelated to time to 20-ppm change. CONCLUSIONS: An abnormal LHBT was found in children with functional symptoms of the digestive tract, but the exact mechanism involved, accelerated intestinal transit or SIBO, needs to be confirmed by an additional method.

Testes Respiratórios/métodos , Doenças Funcionais do Colo , Hidrogênio , Intestino Delgado , Intolerância à Lactose , Lactose , Dor Abdominal/etiologia , Dor Abdominal/fisiopatologia , Adolescente , Criança , Pré-Escolar , Doenças Funcionais do Colo/etiologia , Doenças Funcionais do Colo/fisiopatologia , Feminino , Motilidade Gastrointestinal , Humanos , Hidrogênio/análise , Hidrogênio/metabolismo , Intestino Delgado/metabolismo , Intestino Delgado/fisiopatologia , Lactose/análise , Lactose/metabolismo , Intolerância à Lactose/complicações , Intolerância à Lactose/diagnóstico , Intolerância à Lactose/metabolismo , Intolerância à Lactose/fisiopatologia , Masculino , Estatística como Assunto
Rev. cienc. salud ; 13(1): 33-44, dic. 2009. tab, graf
Artigo em Espanhol | LILACS | ID: lil-567075


In the northern part of Chile, due to its geoclimatic characteristics, enteroparasitosis in school children is mainly due to protozoos is such as Giardiosis and Blastocystosis, and Enterobiosis among helminthic infections. During the years 2006 and 2007, we made an enteroparasitosis survey of 92 school children in grades 1 to 8 in two municipal schools of Antofagasta. The global prevalence rate of parasites and commensals was 83.69%. We found frequencies of 68.48% for Blastocystis hominis, 8.70% for Giardia duodenalis, and 23.91% for Enterobius vermicularis. The frequencies for commensals were 18.48% for Entamoeba coli, 16.30% for Endolimax nana, 5.43% for Chilomastix mesnili and 3.26% for Lodamoeba bütschlii. We conclude that the frequency of infection by parasites and commensals among school children is related to the deficient sanitary conditions present in some sectors of the city of Antofagasta, associated with socioeconomic and cultural factors of the population.

En el norte de Chile por las características geoclimáticas, las enteroparasitosis en escolares se centra principalmente en protozoosis como la Giardiosis y Blastocistosis y la Enterobiosis entre las helmintiasis. Durante los años 2006 y 2007 se encuestó enteroparasitológicamente a 92 escolares que cursaban entre 1° y 8° básico en dos escuelas municipales de Antofagasta. La tasa de prevalencia global por parásitos y comensales fue de 83,69%. Con indicadores de 68,48% para Blastocystis hominis y 8,70% para Giardia duodenalis, y de 23,91% para Enterobius vermicularis. Entre los comensales se encontró Entamoeba coli (18,48%), Endolimax nana (16,30%), Chilomastix mesnili (5,43%) y Iodamoeba bütschlii (3,26%). Se concluye que la frecuencia de infecciones por parásitos y comensales entre los escolares estaría relacionada con las condiciones sanitarias deficitarias presentes en algunos sectores de la ciudad de Antofagasta, asociadas a factores socioeconómicos y culturales de la población.

Humanos , Masculino , Feminino , Criança , Enteropatias Parasitárias/epidemiologia , Estudantes , Distribuição por Idade e Sexo , Estudos Transversais , Chile/epidemiologia , Enterobíase/epidemiologia , Giardíase/epidemiologia , Inquéritos Epidemiológicos , Infecções por Blastocystis/epidemiologia , Prevalência , Fatores Socioeconômicos